For thymic selection and responses to pathogens, T cells interact through their αβ T cell receptor (TCR) with peptide–major histocompatibility complex (MHC) molecules on antigen-presenting cells. How the diverse TCRs interact with a multitude of MHC molecules is unresolved. It is also unclear how humans generate larger TCR repertoires than mice do. We compared the TCR repertoire of CD4 T cells selected from a single mouse or human MHC class II (MHC II) in mice containing the human TCR gene loci. Human MHC II yielded greater thymic output and a more diverse TCR repertoire. The complementarity determining region 3 (CDR3) length adjusted for different inherent V-segment affinities to MHC II. Humans evolved with greater nontemplate-encoded CDR3 diversity than did mice. Our data, which demonstrate human TCR–MHC coevolution after divergence from rodents, explain the greater T cell diversity in humans and suggest a mechanism for ensuring that any V–J gene combination can be selected by a single MHC II.

为了进行胸腺选择和对病原体的反应，T细胞通过其αβT细胞受体（TCR）与抗原呈递细胞上的肽-主要组织相容性复合体（MHC）分子相互作用。尚未解决各种TCR如何与多种MHC分子相互作用的方法。还不清楚人类如何产生比小鼠更大的TCR库。我们在含有人TCR基因位点的小鼠中比较了从单只小鼠或人类MHC II类（MHC II）中选择的CD4 T细胞的TCR库。人类MHC II产生更大的胸腺输出和更多样化的TCR库。针对MHC II的不同固有V段亲和力调整了互补决定区3（CDR3）的长度。与小鼠相比，人类进化出的非模板编码CDR3多样性更大。我们的数据证明了与啮齿动物背离后人类TCR-MHC的共同进化，